The aberrant accumulation of sterols contributes to heart attack and stroke. Two proteins embedded in the membrane of the endoplasmic reticulum, Insig-1 and Insig-2, are key players in the cellular pathway that regulates cellular sterol levels. Ren et al. report the structure of a mycobacterial homolog of Insig. The structure, together with biochemical experiments, suggests how Insig interacts with other components of the sterol regulatory pathway.